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Radiology Oct 1983Lenz-Majewski syndrome is a rare disorder of unknown etiology. The condition is characterized by a disproportionately large head with large fontanels and widely...
Lenz-Majewski syndrome is a rare disorder of unknown etiology. The condition is characterized by a disproportionately large head with large fontanels and widely separated sutures that close late. The head appears large relative to the reduced size of the trunk and limbs. The skin is loose, wrinkled, and atrophic with prominent veins, especially in the scalp. The ears are large and floppy, and frequently there is choanal atresia or stenosis, nasolacrimal duct obstruction, and, in boys, cryptorchidism and inguinal hernia. The disorder is characterized by failure to thrive and mental retardation. In contrast to craniometaphyseal and craniodiaphyseal dysplasias, the conditions most likely to be mistaken for this disorder, there does not appear to be any impingement on cranial nerves. The skeletal alterations are striking. The radiographic features include progressive sclerosis of the skull, facial bones, and vertebrae; broad clavicles and ribs; short or absent middle phalanges; diaphyseal undermodeling and midshaft cortical thickening; metaphyseal and epiphyseal hypostosis; and retarded skeletal maturation. Tooth enamel is also defective.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Humans; Infant, Newborn; Intellectual Disability; Male; Radiography; Skin Abnormalities; Skull; Syndrome
PubMed: 6611917
DOI: 10.1148/radiology.149.1.6611917 -
American Journal of Medical Genetics.... Oct 2019Lenz-Majewski syndrome (LMS) is an extremely rare type of cutis laxa caused by dominant mutations in PTDSS1 gene. We report an Egyptian patient who presented with cutis...
Lenz-Majewski syndrome (LMS) is an extremely rare type of cutis laxa caused by dominant mutations in PTDSS1 gene. We report an Egyptian patient who presented with cutis laxa, brachydactyly, and progeroid features. LMS syndrome was suspected and a previously reported de novo heterozygous missense mutation (c.284G > T, p.R95L) in PTDSS1 was identified. To the best of our knowledge, nine molecularly proven patients with LMS from different ethnicities have been reported. Our patient is the first report from the Middle East and the tenth molecularly proven patient reported to date. His clinical features were in accordance with LMS syndrome. In addition, his hands X-ray images showed hypoplastic or absent middle and proximal phalanges but sparing the thumbs. This hand patterning was similarly observed before. Further, he had relatively large and convex fingernails. Our report highlights this unique hand patterning and suggests these signs should be considered among the diagnostic criteria of LMS. Further reports of patients with PTDSS1 mutations are necessary to further elucidate the detailed clinical features of LMS syndrome.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Egypt; Exons; Humans; Infant; Intellectual Disability; Introns; Male; Nitrogenous Group Transferases; Syndrome
PubMed: 31403251
DOI: 10.1002/ajmg.a.61327 -
Human Mutation Jan 2018Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is...
Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.
Topics: Ciliopathies; Cytoplasmic Dyneins; Genetic Association Studies; Genetic Markers; Genetic Variation; Genotype; Humans; Intercellular Signaling Peptides and Proteins; Mutation; Phenotype; Proteins; Radiography; Skeleton; Exome Sequencing
PubMed: 29068549
DOI: 10.1002/humu.23362 -
European Journal of Medical Genetics Apr 2024Lenz-Majewski hyperostotic dwarfism (LMHD) is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, dysmorphic facial features,...
Lenz-Majewski hyperostotic dwarfism (LMHD) is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, dysmorphic facial features, brachydactyly, symphalangism and cutis laxa. Nineteen cases have been reported in the literature so far, eleven of them with PTDSS1 mutations. Although studies have had clinically similar findings, in some cases the authors have reported even rarer features such as hydrocephalus, facial paralysis, and cleft palate. We, hereby, report the case of the first patient with Lenz-Majewski syndrome (LMS) with molecular confirmation from Turkey. Although our patient had characteristic features described in the literature, she also had immunodeficiency, which has not been reported before. Although there is no established phenotype-genotype correlation, molecular mechanisms can be explained with the reporting of more patients.
Topics: Female; Humans; Intellectual Disability; Short Rib-Polydactyly Syndrome; Bone Diseases, Developmental; Otitis Media; Abnormalities, Multiple
PubMed: 38262577
DOI: 10.1016/j.ejmg.2024.104910 -
Ryoikibetsu Shokogun Shirizu 2000
Review
Topics: Abnormalities, Multiple; Bone and Bones; Craniofacial Abnormalities; Dental Enamel Hypoplasia; Diagnosis, Differential; Dwarfism; Growth Disorders; Humans; Intellectual Disability; Prognosis; Skin Abnormalities
PubMed: 11057197
DOI: No ID Found -
Ryoikibetsu Shokogun Shirizu 2000
Review
Topics: Chromosomes, Human, Pair 4; Diagnosis, Differential; Genes, Recessive; Humans; Infant, Newborn; Prognosis; Radiography; Short Rib-Polydactyly Syndrome
PubMed: 11057233
DOI: No ID Found -
American Journal of Human Genetics Aug 2012Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated... (Comparative Study)
Comparative Study
Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Apoptosis Regulatory Proteins; Base Sequence; Cerebellum; Child; Cleft Palate; Exome; Fetus; Foot Deformities, Congenital; Hand Deformities, Congenital; Hedgehog Proteins; Homozygote; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Molecular Sequence Data; Mutation; Orofaciodigital Syndromes; Phenotype; Sequence Analysis, DNA; Signal Transduction; Young Adult
PubMed: 22883145
DOI: 10.1016/j.ajhg.2012.06.017 -
Orphanet Journal of Rare Diseases Jun 2007Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal dysplasia characterized by short ribs, polydactyly, growth retardation, and ectodermal and heart defects.... (Review)
Review
Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal dysplasia characterized by short ribs, polydactyly, growth retardation, and ectodermal and heart defects. It is a rare disease with approximately 150 cases reported worldwide. The exact prevalence is unknown, but the syndrome seems more common among the Amish community. Prenatal abnormalities (that may be detected by ultrasound examination) include narrow thorax, shortening of long bones, hexadactyly and cardiac defects. After birth, cardinal features are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth. Heart defects, especially abnormalities of atrial septation, occur in about 60% of cases. Cognitive and motor development is normal. This rare condition is inherited as an autosomal recessive trait with variable expression. Mutations of the EVC1 and EVC2 genes, located in a head to head configuration on chromosome 4p16, have been identified as causative. EVC belongs to the short rib-polydactyly group (SRP) and these SRPs, especially type III (Verma-Naumoff syndrome), are discussed in the prenatal differential diagnosis. Postnatally, the essential differential diagnoses include Jeune dystrophy, McKusick-Kaufman syndrome and Weyers syndrome. The management of EVC is multidisciplinary. Management during the neonatal period is mostly symptomatic, involving treatment of the respiratory distress due to narrow chest and heart failure. Orthopedic follow-up is required to manage the bones deformities. Professional dental care should be considered for management of the oral manifestations. Prognosis is linked to the respiratory difficulties in the first months of life due to thoracic narrowness and possible heart defects. Prognosis of the final body height is difficult to predict.
Topics: Adolescent; Adult; Child; Child, Preschool; Diagnosis, Differential; Ellis-Van Creveld Syndrome; Female; Humans; Infant; Infant, Newborn; Membrane Proteins; Mutation; Pregnancy; Prenatal Diagnosis; Prognosis; Proteins; Short Rib-Polydactyly Syndrome
PubMed: 17547743
DOI: 10.1186/1750-1172-2-27 -
British Journal of Plastic Surgery Jul 1984
Topics: Abnormalities, Multiple; Humans; Infant; Male; Orofaciodigital Syndromes
PubMed: 6743912
DOI: 10.1016/0007-1226(84)90107-3 -
Journal of Rare Diseases Research &... 2016Lenz-Majewski syndrome (LMS) is a rare disease presenting with complex physical and mental abnormalities. Whole exome sequencing performed on five LMS-affected...
Lenz-Majewski syndrome (LMS) is a rare disease presenting with complex physical and mental abnormalities. Whole exome sequencing performed on five LMS-affected individuals has identified gain-of-function mutations in the PTDSS1 gene encoding phosphatidylserine synthase 1 (PSS1) enzyme. These mutations all rendered PSS1 insensitive to PS-mediated product inhibition. In a recent study we showed that uncontrolled PS production by these mutant PSS1 enzymes lead to the accumulation of PS in the ER where it is not detected in normal cells. This increased PS in the ER in turn, activated the Sac1 phosphatase, which is responsible for the dephosphorylation of the minor lipid, phosphatidylinositol 4-phosphate (PI4P) in the ER. Increased Sac1 activity decreased PI4P levels both in the Golgi and the plasma membrane thereby dissipating the PI4P gradients set up by PI 4-kinase enzymes (PI4Ks) between these membranes and the ER. Such PI4P gradients at membrane contact sites have been shown to support the transports of structural lipids such as cholesterol and PS out of the ER by non-vesicular lipid transfer. Therefore, uncontrolled production of PS not only affects the PS status of cells but also initiates an avalanche of changes in the metabolism of other membrane lipids via affecting PI4P gradients throughout the cell. Recognition of the close metabolic interaction between PS synthesis and PI4P metabolism provided a new clue to better understand the molecular underpinning of this rare and severe disease.
PubMed: 30854527
DOI: 10.29245/2572-9411/2017/1.1080